The invention relates to processes for the preparation of xcex1-substituted benzylnitroguanidines. The invention further relates to processes for isolation of xcex1-substituted benzylnitroguanidines from aqueous alcoholic compositions.
xcex1-Substituted benzylnitroguanidines can be used as agricultural chemicals to increase crop yields, provide pre-emergent control of weeds, and promote defoliation. Controlled defoliation of plants has important agricultural uses. For example, cotton defoliation prior to harvest eliminates the main source of stain and trash, resulting in better grade cotton.
Speltz et al., U.S. Pat. Nos. 4,594,092, 4,804,780, and 4,944,788, teach the preparation of substituted benzylnitroguanidines by reacting a substituted benzylamine with 2-alkyl-1 (or 3)-nitro-2-thiopseudourea and isolating the solid product by filtration. Speltz et al. also teach the preparation of substituted benzylnitroguanidines by reacting a substituted benzylamine with N-alkyl-N-nitroso-Nxe2x80x2-nitroguanidine in the presence of an aqueous aliphatic alcohol solution, followed by removal of the precipitate by filtration and washing of the solid product.
Arotin et al., U.S. Pat. Nos. 4,639,268 and 5,175,365, teach the preparation of substituted benzylnitroguanidines by reacting a substituted benzylamine with a 1-alkyl-3-nitro-1-nitrosoguanidine in the presence of an aqueous aliphatic alcohol solution, followed by removal of the precipitate by filtration and washing of the solid product.
Unfortunately, many prior art processes include steps of filtering and washing substituted benzylnitroguanidines, and such step can result in a loss of product. Additionally, many prior art processes require the use of large amounts of solvents.
There is a need for processes for preparing a-substituted benzylnitroguanidines which do not require the filtering and washing of the xcex1-substituted benzylnitroguanidines. It would be desirable if the processes did not require the use of large amounts of solvents.
Accordingly, it is an object of the present invention to obviate problems of the prior art.
It is a further object of the present invention to provide processes for preparing xcex1-substituted benzylnitroguanidines which do not require the filtering and washing of the xcex1-substituted benzylnitroguanidines.
It is a another object of the present invention to provide processes for isolating xcex1-substituted benzylnitroguanidines from aqueous alcoholic compositions which do not require the filtering and washing of the xcex1-substituted benzylnitroguanidines
According to one aspect of the invention there are provided processes for preparing xcex1-substituted benzylnitroguanidines having the formula (I): 
wherein R is an unsubstituted or an OHxe2x80x94or OCH3-substituted C1-C3 alkyl, CH2OCH3, C6H5, CH2C6H5, or CH2CHxe2x95x90CH2; and W, X, Y, Z are each individually hydrogen, halogen, OH, straight or branched chain C1-C4 alkyl, straight or branched chain C1-C4 alkoxy; CF3, C(OH)2CF3, OCHF2, OCF3, NO2, OCF2CHF2, N(CH3)2, CH2N(CH3)2, CH2NH2, CH2CH2COOC2H5, C6H4, CH2OH, CH2OCH3, COOCH3, CH2CH2COOC2H5, OC6H5, OSO2CH3, SCH3, CN, CH2CN or tetrahydro-H-pyran-2-yl; and the salts, tautomers and optical isomers thereof.
The processes for preparing the xcex1-substituted benzylnitro-guanidines comprise the steps of:
(a) providing a reaction mixture comprising water, alcohol, an S-alkyl nitroisothiourea, and an xcex1-substituted benzylamine;
(b) heating the reaction mixture;
(c) steam distilling the alcohol from the reaction mixture; and
(d) isolating an xcex1-substituted benzylnitroguanidine from the remaining water layer.
According to another aspect of the invention there are provided processes for preparing xcex1-substituted benzylnitroguanidine, comprising the steps of:
(a) providing a reaction mixture comprising S-methyl nitroisothiourea, xcex1-substituted benzylamine, water and alcohol;
(b) heating the reaction mixture;
(c) steam distilling the alcohol from the reaction mixture; and
(d) filtering an xcex1-substituted benzylnitroguanidine from the remaining water layer.
According to a further aspect of the invention there are provided processes for isolating of an xcex1-substituted benzylnitroguanidine from a composition comprising water, alcohol and xcex1-substituted benzylnitroguanidines, comprising the steps of:
(a) steam distilling the alcohol from the composition; and
(b) filtering the 1-(xcex1-ethylbenzyl)-3-nitroguanidine from the remaining water layer.
These and additional aspects, objects and advantages of the invention are more fully described in the following detailed description.
The present invention is directed to processes for the preparation of xcex1-substituted benzylnitroguanidines and processes for isolation of xcex1-substituted benzylnitroguanidines from aqueous alcoholic compositions.
The xcex1-substituted benzylnitroguanidines which may be prepared using processes in accordance with the invention include compounds of the formula (I): 
wherein R is a C1-C3 alkyl optionally substituted with OH or OCH3;
CH2OCH3, C6H5, CH2C6H5, or CH2CHxe2x95x90CH2; and W, X, Y, Z are each individually hydrogen, halogen, OH, straight or branched chain C1-C4 alkyl, straight or branched chain C1-C4 alkoxy; CF3, C(OH)2CF3, OCHF2, OCF3, NO2, OCF2CHF2, N(CH3)2, CH2N(CH3)2, CH2NH2, CH2CH2COOC2H5, C6H4, CH2OH, CH2OCH3, COOCH3, CH2CH2COOC2H5, OC6H5, OSO2CH3, SCH3, CN, CH2CN or tetrahydro-H-pyran-2-yl; and the salts, tautomers and optical isomers thereof.
The xcex1-substituted benzylnitroguanidine salts include inorganic salts, such as alkali metal, alkaline earth metal, Co, Cu, Zn, and Ag salts, and organic amine salts, such as ammonium compounds having the structure, N+ Ra Rb Rc Rd, wherein Ra, Rb, Rc, and Rd are each independently selected from hydrogen and C1-C30 straight or branched chain alkyl optionally substituted with one or two OH, C3-C6 alkenyl or C3-C6 alkynyl groups. Preferred salts include the sodium, calcium, magnesium, potassium, ammonium, methylamine, trimethylamine, dodecylamine, tributylamine, diisopropylamine, triethylamine, tetrabutylamine, and tallow-amine salts of the substituted guanidine.
In one embodiment R is CH3, C2H5, CF3, n-C3 H7, CH2OCH3 or CH2CHxe2x95x90CH2. In another embodiment R is CH3, CF3, C2H5, or C6H5. In one preferred embodiment R is C2H5.
In one embodiment W, X, Y, Z are each individually hydrogen, halogen, OH, straight or branched chain C1-C4 alkyl, straight or branched chain C1-C4 alkoxy; CH2OH, or CH2OCH3. In another embodiment W, X, Y, Z are each individually hydrogen, halogen, OH, OCH3, OC2H5, OC3H7-n, OC4H9-sec, OCF3, F, Cl, Br, I, CH3, C2H5, CF3, or CN. In one preferred embodiment W, X, Y and Z are all hydrogen.
In one embodiment the xcex1-substituted benzylnitroguanidines prepared using processes in accordance with the invention are selected from the group consisting of (+)isomers, (xe2x88x92)-isomers and mixtures thereof of compounds having the formula (I) wherein R is CH3, C2 H5, CF3, n-C3H7, CH2 OCH3 or CH2CHxe2x95x90CH2; W is hydrogen, o-F, m-F, p-F, m-OCH3, m-OH or p-Cl; and X, Y, and Z are all hydrogen, and the salts, tautomers and optical isomers thereof.
Examples of xcex1-substituted benzylnitroguanidines include 1-(xcex1-methylbenzyl)-3-nitroguanidine, 1-(xcex1-ethylbenzyl)-3-nitroguanidine, 1-(xcex1-ethyl-m-fluorobenzyl)-3-nitroguanidine, 1-(xcex1-ethyl-m-methoxybenzyl)-3-nitroguanidine, 1-(o-fluoro-xcex1-methylbenzyl)-3-nitroguanidine, 1-(p-fluoro-xcex1-methylbenzyl)-3-nitroguanidine, 1-(xcex1-trifluoromethylbenzyl)-3-nitroguanidine, 1-(xcex1-propylbenzyl)-3-nitroguanidine, 1-(xcex1-methyoxymethyllbenzyl)-3-nitroguanidine, and 1-(xcex1-allylbenzyl)-3-nitroguanidine.
In one preferred embodiment the xcex1-substituted benzylnitroguanidine compound is 1-(xcex1-ethylbenzyl)-3-nitroguanidine. The 1-(xcex1-ethylbenzyl)-3-nitroguanidine may be the (+) isomeric form, the (xe2x88x92) isomeric form or a mixture of the (+) and (xe2x88x92) isomeric forms. In a more preferred embodiment the guanidine compound is (+)-1-(xcex1-ethylbenzyl)-3-nitroguanidine.
The xcex1-substituted benzylnitroguanidine is formed by reacting an S-alkyl nitroisothiourea with xcex1-substituted benzylamine, as set forth in the reaction below: 
Processes in accordance with the present invention comprise the step of preparing a reaction mixture comprising water, alcohol, an S-alkyl nitroisothiourea and an xcex1-substituted benzylamine having the formula (II) 
wherein R is a C1-C3 alkyl optionally substituted with OH or OCH3; CH2OCH3, C6H5, CH2C6H5, or CH2CHxe2x95x90CH2; and W, X, Y, Z are each individually hydrogen, halogen, OH, straight or branched chain C1-C4 alkyl, straight or branched chain C1-C4 alkoxy; CF3, C(OH)2CF3, OCHF2, OCF3, NO2, OCF2CHF2, N(CH3)2, CH2N(CH3)2, CH2NH2, CH2CH2COOC2H5, C6H4, CH2OH, CH2OCH3, COOCH3, CH2CH2COO OC6H5, OSO2CH3, SCH3, CN, CH2CN or tetrahydro-H-pyran-2-yl; heating the reaction mixture; steam distilling the alcohol from the reaction mixture; and filtering the xcex1-substituted benzylnitroguanidine from the remaining water layer.
In one embodiment the xcex1-substituted benzylamine has the formula (II) wherein R is CH3, C2H5, CF3, n-C3 H7, CH2OCH3 or CH2CHxe2x95x90CH2, preferably CH3, CF3, C2H5, or C6H5, more preferably R is C2H5. In one embodiment W, X, Y, Z are each individually hydrogen, halogen, OH, straight or branched chain C1-C4 alkyl, straight or branched chain C1-C4 alkoxy; CH2OH, or CH2OCH3, while in another embodiment W, X, Y, Z are each individually hydrogen, halogen, OH, OCH3, OC2H5, OC3H7-n, OC4H9-sec, OCF3, F, Cl, Br, I, CH3, C2H5, CF3, or CN. Preferably W, X, Y and Z are all hydrogen.
In one embodiment the xcex1-substituted benzylamine has the formula (II) wherein R is CH3, C2 H5, CF3, n-C3H7, CH2 OCH3 or CH2CHxe2x95x90CH2; W is hydrogen, o-F, m-F, p-F, m-OCH3, m-OH or p-Cl; and X, Y, and Z are all hydrogen, and the salts, tautomers and optical isomers thereof. In one preferred embodiment the xcex1-substituted benzylamine is xcex1-ethylbenzyl-amine.
Suitable S-alkyl nitroisothiourea include S-C1-C4-alkyl nitroisothio-urea, preferably S-methyl nitroisothiourea.
Alcohols suitable for use in processes in accordance with the invention include aliphatic alcohols such as methanol, ethanol and propanol and combinations thereof. Ethanol and combinations of ethanol with other aliphatic alcohols are preferred, and the use of ethanol alone is most preferred. The water and the alcohol together form a solvent comprising from about 3% to about 80%, more preferably 5% to about 60%, by volume water and from about 20% to about 97%, more preferably about 40% to about 95%, by volume alcohol. In one embodiment of the invention the alcohol is ethanol, and the solvent comprises about 5% water and about 95% ethanol.
Processes in accordance with the invention are advantageous in that large amounts of alcohol are not required. As used herein, xe2x80x9clarge amounts of alcoholxe2x80x9d is intended to refer to a level of more than about 1 kilogram of alcohol per mole of S-alkyl nitroisothiourea.
In one embodiment of the invention the reaction mixture comprises less than about 700, preferably less than about 500, more preferably less than about 300, grams alcohol per mole of S-alkyl nitroisothiourea. In one embodiment of the invention the reaction mixture comprises less than about 200, preferably less than about 175, grams water per mole of S-alkyl nitroisothiourea.
Any suitable reactor may be used for preparing and heating the reaction mixture. In one embodiment the reactor is fitted with a vent line to an agent which can capture or absorb the alkyl mercaptan released during the reaction, preferably the reactor is fitted with a vent line to an aqueous caustic solution which absorbs the alkyl mercaptan. Suitable caustic solutions include solutions comprising water and a base selected from the group consisting of alkali metal hydroxides and combinations thereof. The caustic solution may comprise from about 10% to about 30% base.
The reaction mixture may be prepared by charging the reaction with the s-alkyl nitroisothiourea, water and alcohol, and adding the xcex1-substituted benzylamine at a rate such that the reaction mixture remains at a temperature of no more than about 80xc2x0 C., preferably less than about 40xc2x0 C., more preferably less than about 30xc2x0 C., throughout the addition of the xcex1-substituted benzylamine. The react mixture may be stirred at temperature of no more than about 80xc2x0 C., preferably less than about 40xc2x0 C., more preferably less than about 30xc2x0 C., for a period of time of from about 10 to about 60 minutes, preferably from about 20 to about 40 minutes, more preferably about 30 minutes prior to heating.
The step of heating the reaction mixture typically comprises heating the reaction mixture to a time and for a time sufficient for the xcex1-substituted benzylnitroguanidine to be formed. In one embodiment the reaction mixture is heated to reflux, and maintained at reflux for a period of from about 1 to about 8 hours, preferably from about 4 to about 6 hours.
Any suitable steam distillation apparatus may be used for steam distilling the alcohol from the reaction mixture. The alcohol that is removed by the steam distillation may be purified, dried and recycled.
Removal of the alcohol results in a remaining water layer which comprises the xcex1-substituted benzylnitroguanidine. The xcex1-substituted benzylnitroguanidine may be isolated from the water layer using any suitable procedure, such as filtration. Any suitable filtration apparatus may be used for filtering the xcex1-substituted benzylnitroguanidine from the water layer. The step of filtering the xcex1-substituted benzylnitroguanidine from the water layer may be performed at atmospheric pressure or under vacuum. Suitable pressures for filtering are from about 150 to about 750 mm Hg, preferably from about 150 to about 400 mm Hg, more preferably from about 150 to about 250 mm Hg.
The steps of steam distilling and isolating the xcex1-substituted benzylnitroguanidines from water, preferably by filtering, are not limited to synthesis methods using S-alkyl nitroisothiourea and xcex1-substituted benzylamine. The steps may be used to isolate xcex1-substituted benzylnitroguanidines from any aqueous alcoholic composition.